Kidney diseases are defined as diseases associated with primary or secondary renal disorders and are treated by diet therapy, therapeutic exercises, or pharmaceutical agents. Dialysis treatment or kidney transplantation may be needed as symptoms advance. Thus, there is a demand for more effective therapeutic agents.
Pathological features of progressive glomerular disorders include the growth of mesangial cells and glomerulosclerosis. Thickening of the glomerular basement membrane and mild increase in glomerular size are observed at the early stage of diabetic nephropathy. Diffuse expansion of mesangial matrix is observed several years after onset. This phenomenon is assumed to be caused by an abnormal increase of extracellular matrix proteins such as type IV and I collagens, fibronectin, and laminin. Abnormal remodeling of the matrix is also found in glomerular mesangial cells in kidney diseases such as IgA nephropathy or Alport's syndrome, and is known to eventually lead to glomerulosclerosis. Thus, the abnormal increase of mesangial matrix is closely involved in diseases associated with glomerulosclerosis.
In diabetic nephropathy, the mechanism underlying the overproduction of type IV collagen, which is a mesangial matrix protein, has been reported to have a number of pathways. Various molecules are assumed to be involved in the overproduction. Transforming growth factor-β (TGF-β) activates Smad2 and Smad3 via activin receptor-like kinase 5 (ALK5), a type I receptor, resulting in overproduction of extracellular matrix proteins such as α1 type IV collagen (Non-Patent Document 1). Smad1 has been demonstrated to be directly involved in the overproduction of type IV collagen (Patent Document 1). Smad1 is known to be a member of the bone morphogenetic protein (BMP) signaling system. BMP activates Smad1 via the type I receptors ALK2, 3, and 6, thereby regulating the transcription of target genes (Non-Patent Document 2). In addition to Smad1, Smad5 and Smad8 are involved in BMP signaling. Smad1 transduces the TGF-β signal via ALK1 in endothelial cells, hematopoietic cells, and the like, thereby participating in the transcriptional regulation of target genes (Non-Patent Document 3).
Suppressing the overproduction of mesangial matrix proteins is expected to ameliorate kidney diseases including diabetic nephropathy. As described above, however, the mechanism underlying the overproduction of mesangial matrix proteins including type IV collagen is complicated, and to date, it is unknown what pathway made of which combination of members contributes to this overproduction.    Patent Document 1: WO2005/026344    Non-Patent Document 1: Li J. H. et al., Kidney International, (2003) 63, 2010-2019    Non-Patent Document 2: Zwijsen A. et al., FEBS Letters (2003) 546, 133-139    Non-Patent Document 3: Goumans M. J. et al., EMBO J., (Apr. 2, 2002) 21(7), 1743-53